Structure of the JAK2 protein.
In the 2 decades since the discovery of the JAK-STAT signaling pathway, intense research has resulted in its becoming one of the best-understood signal transduction cascades.
However, it is only in recent years that cancer researchers have begun to enjoy the fruits of this research, and even now JAK inhibitors are in their infancy compared with other targeted therapies. The development of these agents may offer new hope, particularly for treatment-resistant forms of chronic leukemia.
The Basics of JAK/STAT Signaling
Found in slime molds and humans alike, JAK-STAT signaling is relatively simple, as signal transduction pathways go. There are 3 principal components: a receptor, a member of the Janus kinase (JAK) family, and a member of the signal transducer and activator of transcription (STAT) family. This pathway handles incoming signals from a number of different membrane receptors, most importantly the cytokine receptors.
Named originally for the 2-faced god of Roman mythology, JAK is involved in signal transduction in both normal cells and disease states. It was often referred to as “Just Another Kinase” because its role initially was not fully defined. We now know that there are 4 members of the JAK family of nonreceptor tyrosine kinases: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2).
Once activated, the JAKs phosphorylate their major target, the STATs, of which there are 7. The STATs are transcription factors that normally lie dormant in the cytoplasm, but when phosphorylated they move into the nucleus where they bind to specific DNA sequences and drive or inhibit the suppression of target genes.
This relatively simple mechanism offers a means of directly translating incoming signals from outside the cell into cellular responses much more quickly than other signal transduction pathways, with each particular type of receptor-JAK-STAT combination driving a specific response. What is more complex and less well-understood is the considerable crosstalk between JAK-STAT and other signaling pathways.
Key elements of the JAK-STAT pathway
Click to enlarge.
Important in Hematopoiesis, Blood Cancer
JAK activation stimulates numerous cellular processes, including proliferation, differentiation, migration, and apoptosis. It plays a particularly important role in the formation and development of blood cells (hematopoiesis) and in proper immune function. Aberrant JAK-STAT signaling is therefore implicated in the development of blood cancer.
It was not until 2005 that mutations in the JAK
gene were directly linked to the development of cancer, with the identification of the V617F point mutation in JAK2
. This defect has subsequently been shown to be important in the development of myeloproliferative neoplasms (MPNs), characterized by the overproduction of blood cells.
The MPNs can be further characterized by the presence or absence of the Philadelphia chromosome, a chromosomal abnormality in which parts of chromosomes 9 and 22 break off and exchange places. The result is that 2 genes, breakpoint cluster region (BCR
) and Abelson tyrosine kinase (ABL), form the oncogenic BCR-ABL
The treatment of MPNs initially showed promise with the development of targeted therapies such as gefitinib (Iressa, AstraZeneca) and imatinib (Gleevec, Novartis). However, patients with the 3 Philadelphia chromosome-negative forms of MPN, namely myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET), were resistant to these treatments. The JAK2
V617F mutation has been detected in >80% of PV cases, from about 40% to 70% of ET cases, and from about 40% to 60% of MF cases.
The main source of morbidity and mortality in patients with MPN is the development of thrombotic and hemorrhagic events and the risk of transformation to acute myeloid leukemia (AML), which has a particularly poor prognosis. With the exception of stem cell transplants, there are currently no curative treatments for these disorders.
Thus, the discovery that JAK-STAT signaling is frequently perturbed in these forms of MPN was an exciting and important breakthrough. In the 6 years since, a number of biotech companies have streamlined JAK2 inhibitor development, and these compounds have already demonstrated dramatic improvements in quality of life and reduction of spleen size in a significant proportion of patients participating in clinical trials.